What is the recommended treatment regimen for a patient requiring Zerbaxa (ceftolozane and tazobactam) for an infection, considering potential renal impairment?

Zerbaxa (Ceftolozane-Tazobactam) Dosing in Renal Impairment

For patients with normal renal function, administer Zerbaxa 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) intravenously every 8 hours as a 1-hour infusion; dose adjustments are mandatory for moderate-to-severe renal impairment to maintain therapeutic efficacy while avoiding toxicity. 1

Standard Dosing for Normal Renal Function

• Adults with normal renal function (CrCl >50 mL/min): Zerbaxa 1.5 g IV every 8 hours for complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) 1, 2
• Higher doses for hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP): Zerbaxa 3 g (ceftolozane 2 g/tazobactam 1 g) IV every 8 hours 1
• Infusion time: Administer as a 1-hour intravenous infusion 1, 2

Renal Impairment Dosing Algorithm

Mild Renal Impairment (CrCl 50-80 mL/min)

• No dose adjustment required 1
• Ceftolozane exposure increases only 1.26-fold and tazobactam 1.3-fold compared to normal renal function 1
• Monte Carlo simulations demonstrate ≥91% target attainment for bactericidal activity at standard dosing 3

Moderate Renal Impairment (CrCl 30-50 mL/min)

• Reduce dose to 750 mg (ceftolozane 500 mg/tazobactam 250 mg) IV every 8 hours 1, 4
• Ceftolozane exposure increases 2.5-fold and tazobactam 2-fold without adjustment 1, 4
• This adjusted regimen achieves ≥93% bactericidal target attainment up to MIC of 8 mg/L 3

Severe Renal Impairment (CrCl 15-29 mL/min)

• Reduce dose to 375 mg (ceftolozane 250 mg/tazobactam 125 mg) IV every 8 hours 1, 4
• Without adjustment, ceftolozane exposure increases 5-fold and tazobactam 4-fold 1
• Dose-normalized exposure increases 4.4-fold for ceftolozane and 3.8-fold for tazobactam 4

End-Stage Renal Disease (ESRD) on Hemodialysis

• Loading dose: 750 mg (ceftolozane 500 mg/tazobactam 250 mg) IV as a single dose 1
• Maintenance dose: 150 mg (ceftolozane 100 mg/tazobactam 50 mg) IV every 8 hours for the remainder of treatment 1
• Critical timing: Administer dose at the earliest possible time following completion of hemodialysis 1
• Rationale: Approximately two-thirds (66% ceftolozane, 56% tazobactam) of the administered dose is removed by hemodialysis 1, 4

Augmented Renal Clearance (ARC)

• No dose adjustment needed for CrCl ≥180 mL/min 1
• Mean terminal half-life in critically ill patients with ARC: ceftolozane 2.6 hours, tazobactam 1.5 hours 1
• Monte Carlo simulations show ≥91% achieve bactericidal activity up to MIC 4 mg/L with standard 1 g ceftolozane dose in ARC patients 3

Pediatric Dosing Considerations

Standard Pediatric Dosing (eGFR >50 mL/min/1.73 m²)

• Recommended dose: 35 mg/kg IV every 8 hours for critically ill septic children with multidrug-resistant Pseudomonas aeruginosa 5
• Maximum dose: Do not exceed adult dose equivalents 1

Pediatric Severe Renal Impairment

• Reduced dose: 10 mg/kg IV every 8 hours for children with severe acute kidney injury 5
• Insufficient data: There is inadequate information for pediatric patients with eGFR ≤50 mL/min/1.73 m² 1

Pediatric Continuous Renal Replacement Therapy (CRRT)

• Recommended dose: 30 mg/kg IV every 8 hours for patients with high effluent rates 5
• CRRT clearance approximately 0.39 L/h in case reports 5

Pharmacokinetic Principles

• Elimination: Ceftolozane >95% excreted unchanged in urine; tazobactam >80% excreted as parent compound 1
• Renal clearance mechanism: Ceftolozane eliminated via glomerular filtration; tazobactam is a substrate for OAT1 and OAT3 transporters 1
• Half-life: Ceftolozane 3-4 hours, tazobactam 2-3 hours in normal renal function 1
• Protein binding: Ceftolozane has low plasma protein binding (20%) 2

Monitoring Requirements

• Baseline assessment: Obtain creatinine clearance before initiating therapy 1
• Ongoing monitoring: Reassess renal function if clinical status changes, particularly in critically ill patients 4
• No therapeutic drug monitoring required: Unlike aminoglycosides, routine serum concentration monitoring is not necessary 1

Clinical Outcomes in Renal Impairment

• Moderate RI patients have lower cure rates overall: In cIAI trials, response rates were numerically lower in moderate RI patients regardless of treatment (48% ceftolozane/tazobactam vs 69% meropenem in microbiological intent-to-treat) 6
• cUTI outcomes more favorable: Response rates in moderate RI cUTI patients were 81% with ceftolozane/tazobactam versus 78% with levofloxacin 6
• Microbiologically evaluable populations: When excluding indeterminate responses, cure rates were similar between treatments in moderate RI (cIAI: 72.7% vs 71.4%; cUTI: 87% vs 80%) 6

Common Pitfalls to Avoid

• Failure to adjust for moderate impairment: Even CrCl 30-50 mL/min requires dose reduction; exposure increases 2.5-fold without adjustment 1, 4
• Incorrect timing with hemodialysis: Always administer after dialysis to prevent premature drug removal and facilitate directly observed therapy 1
• Overlooking elderly patients: Dosage adjustment should be based on renal function, not age alone, but elderly patients often have reduced CrCl requiring adjustment 1
• Using estimated GFR instead of CrCl: Dosing recommendations are based on creatinine clearance calculations, not eGFR 1

Special Populations

Hepatic Impairment

• No dose adjustment required: Zerbaxa does not undergo hepatic metabolism 1

Pregnancy and Lactation

• Limited data available: Safety profile similar to other cephalosporins with most common adverse effects being nausea, diarrhea, headache, and pyrexia 2